Longitudinal changes in LIC and other parameters in patients receiving different chelation regimens: Data from LICNET.

OBJECTIVES: The liver remains the primary site of iron storage, with liver iron concentration (LIC) being a strong surrogate of total body iron. MRI-R2 can accurately measure LIC. The LICNET (Liver Iron Cutino Network) was established to diagnostics of liver iron overload by MRI-R2 subjects with hemochromatosis in hematological disorders. The aims of the study were to look at variation in LIC measurements during time across different chelation regimens. METHODS: This was a cross-sectional study of 130 patients attending 9 Italian centers participating in the LICNET. LIC comparisons over time (T0 and T1 ) were made using t test and/or Wilcoxon test. RESULTS: LIC significantly decreased from MRI1 to MRI2 although at high variance (median change -0.8 mg Fe/g dw, range: -29.0 to 33.0; P = .011) and 7.7% of patients shifted from LIC values of high risk (>15 mg Fe/g dw) to an intermediate-risk category (7-15 mg Fe/g dw). Median change in LIC and correlation with serum ferritin levels (SF), during different chelation regimens, is reported. CONCLUSIONS: These findings suggest as longitudinal variation in the LIC is possible, across all chelation regimens. It confirms as SF levels not always can be used for estimating changes in LIC.

Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies.

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.

The role of anaemia in oxidative and genotoxic damage in transfused ß-thalassaemic patients.

OBJECTIVES: Redox imbalance and genotoxic damage are commonly observed in ß thalassaemic patients. The aim of this study was to assess the role of anaemia in oxidative and genotoxic damage in regularly transfused thalassaemic patients, undergoing iron chelation therapy. METHODS: We studied the relationships of haematological, biochemical and clinical parameters with oxidative (reactive oxygen species and 8-oxo-7,8-dihydro-2'-deoxyguanosine) and genotoxic biomarkers (Comet assay and cytokinesis-block micronucleus test) in blood samples from 105 patients. To reduce the early effect of redox-active iron, samples were collected when pharmacokinetics of the iron chelators ensured their maximum effectiveness. The transfusion regimen, cardiac and hepatic magnetic resonance imaging T2* were evaluated to characterize the patient cohort. Labile plasma iron (LPI) was also assayed. RESULTS: Haemoglobin level had a significant effect on ROS, %DNA in the tail and micronuclei-micronucleated cell frequency (p < 0.05). Higher Hb values reduced redox imbalance. LPI, detectable in 50.5% of patients, was related to the number of apoptotic and necrotic lymphocytes (p = 0.03), demonstrating the cytotoxic effect of iron. DISCUSSION: The results highlight that an adequate transfusion regimen is essential to limit oxidative and genotoxic damage in ß-thalassemic patients undergoing chelation therapy. CONCLUSION: Owing to the higher risk of cancer in the thalassaemic cohorts, specific genotoxicity/oxidative biomarkers should be monitored in order to ameliorate and formulate more personalized disease management.